TY - JOUR AU - Christophers, Enno AB - BackgroundActinic keratoses (AKs) are precancerous epidermal lesions found most frequently on areas of the skin exposed to the sun. Several case studies published recently have indicated that 5% imiquimod cream, currently licensed for the treatment of genital warts, may be an effective treatment for AK.ObjectiveTo assess the efficacy and safety of imiquimod for the treatment of AK.DesignPatients in this randomized, double-blind, vehicle-controlled study applied 5% imiquimod cream or vehicle to AK lesions 3 times per week for a maximum of 12 weeks or until lesions had resolved. In the event of an adverse reaction, application of imiquimod was reduced to 1 or 2 times per week. Rest periods were also allowed if necessary.SettingA specialized outpatient dermatology clinic within a state-funded hospital in Germany.PatientsThe study population was aged 45 to 85 years. Of 52 patients screened, 36 men and women with AK confirmed by histological diagnosis were enrolled. Patients were excluded from the study if they did not have a histological diagnosis for AK, if they were older than 85 years, or if they did not comply with the protocol. All patients had responded to a notice asking for volunteers.Main Outcome MeasuresThe number and appearance of lesions were evaluated before, during, and after treatment. All adverse effects were recorded.ResultsLesions treated with 5% imiquimod cream were clinically cleared in 21 (84%) of 25 patients and partially cleared in 2 (8%). Clearance was histologically confirmed 2 weeks after the last application of imiquimod in all patients clinically diagnosed as lesion free. Only 10% of patients treated with imiquimod were clinically diagnosed with recurrence 1 year after treatment. No reduction in the size or number of AK lesions was observed in vehicle-treated patients. Adverse effects reported by patients treated with imiquimod included erythema, edema, induration, vesicles, erosion, ulceration, excoriation, and scabbing. However, imiquimod was well tolerated since all patients completed the 12-week treatment. Only a few, mild adverse reactions to the vehicle cream were reported.ConclusionApplication of 5% imiquimod cream for 12 weeks is an effective and well-tolerated treatment for AK.ACTINIC KERATOSES (AKs) are red, scaling epidermal papules that arise on skin overexposed to the sun. Overexposure to ultraviolet light is the main cause for the development of AKs.A 1999 study by Guenthner et alreported that 97% of squamous cell carcinomas (SCCs), a form of nonmelanoma skin cancer (NMSC), were associated with a contiguous AK lesion. However, only a small proportion of AKs progress to invasive cancer. The lifetime risk of progression of an individual AK lesion to invasive SCC is estimated to be between 6% and 10%.Metastatic SCC can be fatal, and causes the majority of the 1300 to 2300 NMSC-associated deaths per year in the United States.As it is impossible to tell which lesions may progress to SCC, it is important that all AKs be treated at an early stage.Therapies for AK include cryosurgery, curettage (with and without electrosurgery), topical application of fluorouracil, dermabrasion, and laser therapy. Chemical peels such as trichloroacetic acid can also remove lesions. Cryosurgery and curettage are the most commonly used treatments, and cryosurgery is currently considered the standard treatment for individual AK lesions.All therapies currently prescribed can be painful and may result in scarring and changes in skin pigmentation.We recently published a case study that demonstrated that the immune-response modifier imiquimod (Aldara; 3M Pharmaceuticals, St Paul, Minn), currently licensed for the treatment of genital warts,may be an effective treatment for AK; application of 5% imiquimod cream for 6 to 8 weeks resolved all treated AK lesions in 6 patients.Imiquimod belongs to a new class of drugs that act by up-regulating the cell-mediated immune response in the skin. In preclinical studies, applications of the immune-response modifier increased the production of the two TH1 cytokines interferon α (IFN-α) and tumor necrosis factor α (TNF-α) in the dermis.Imiquimod has been used successfully for the treatment of various dermatologic conditions including basal cell carcinoma,Bowen disease,lentigo maligna,molluscum contagiosum,verrucae vulgares,and stucco keratosis.Our randomized, double-blind, vehicle-controlled study aimed to assess the efficacy and safety of topically applied 5% imiquimod cream for the treatment of AK. Lesions treated with imiquimod or vehicle cream were assessed for clearance 2 weeks after the final application of the cream and 1 year after treatment.METHODSSTUDY POPULATIONThe study population was composed of men and women aged 45 to 85 years. Each patient had 3 to 10 AK lesions in a treatment area that did not exceed 20 cm2. All patients included in the study had responded to a notice asking for volunteers, and many of those previously treated for AK were unhappy with the treatment they had received. Individuals were excluded if they had been:using interferon/interferon inducers, immunomodulators, immunosuppressants, cytotoxic drugs, or investigational drugs less than 4 weeks before the start of the trial, or treated with any topical therapy for AK lesions less than 2 weeks before that date;diagnosed as having a bacterial or viral infection less than 2 weeks before that date;previously treated or were currently living with a patient being treated with imiquimod;diagnosed as allergic to components of the vehicle cream;diagnosed as having cardiovascular, hematologic, hepatic, neurologic, renal, endocrine, vascular, or gastrointestinal abnormalities or diseases; were taking immunosuppressant medication; or were dependent on alcohol or other drugs.NUMBER OF PATIENTS REQUIREDThe minimum number of patients needed for statistical significance was based on previously published AK treatment studies. The rate of spontaneous healing for AK, which depends on the observation period, was reported to be 5% over 1 month but 18% over 7 months.Therefore, a minimum of 36 patients (24 treated with imiquimod and 12 controls) were required to provide the 95% power needed to detect a significant difference in lesion clearance rates in this 14-week study. These figures were based on a projected clearance rate of 70% for patients treated with imiquimod and 8% for patients treated with the vehicle. Based on the dropout rate of other studies, approximately 44 patients were needed to initiate the study if 36 were to complete it.STUDY DESIGNThis study was randomized and double-blind. Three weeks before treatment was initiated, study subjects had vital signs such as sitting blood pressure, pulse, respiration, and temperature assessed during a physical examination. Urine and blood samples were collected for a range of laboratory tests that included pregnancy testing for female participants. The investigator then recorded each individual's medical history, including all previous treatments for AK, and the 3 to10 lesions selected for treatment were measured and photographed. The treatment area did not exceed 20 cm2. Lesions located on the scalp, forehead, dorsal forearm, neck, or the back of the hand could be included. The exact location of each lesion was recorded on a preprinted diagram of the body and in each patient a biopsy specimen was taken from one of these target lesions to confirm diagnosis. Each participant also signed a statement of informed consent.At a second pretreatment visit vital signs were again examined, serum samples were collected for pregnancy testing, and the creams were dispensed. The creams were presented in 12 sachets of either the trial drug, 5% imiquimod, or the vehicle cream (9 sachets for 3 weeks of treatment, plus 3 extra sachets) prepared by 3M Medica, Borken, Germany. Each sachet contained enough cream to treat a skin area of 20 to 30 cm2. The initial application was supervised by trial staff. Trial subjects were instructed to apply the cream on an area containing 3 to10 lesions 3 times per week for 12 weeks, or until the lesions healed. The cream was left on the skin overnight (for 8 ± 2 hours), and then washed off. Recurrent lesions could be treated again; however, the length of treatment did not exceed 12 weeks.Patients were assessed at weeks 2, 3, 6, 9, and 12 after treatment initiation. At each visit vital signs were recorded, AK lesions were photographed, and local and systemic adverse or abnormal effects that had occurred in the intervening weeks were assessed and recorded. The incidence and severity of erythema, edema, induration, vesicles, erosion, ulceration, excoriation or flaking, and scabbing was recorded on a scale of 1 to 3, with 1 representing a mild and 3 a severe reaction. Systemic reactions were assessed by asking patients how they had felt since their last treatment. Patients who experienced severe adverse reactions were allowed rest periods of up to 3 weeks, after which the frequency of applications was reduced to 1 or 2 times per week. Patients who discontinued treatment because of prolonged severe side effects, a clinically significant lesion increase in the treated area, a lack of therapeutic effect, an adverse experience, or an anomaly reported by the laboratory were not replaced. Noncompliant patients were dropped from the trial.At week 14, 2 weeks after the final dose of cream was applied, a clinical evaluation of the AK lesions was made and a second sample was taken from the AK lesion where the initial biopsy was made. Clinical clearance based on observation was confirmed if tissue from the posttreatment biopsy was found to be normal. All biopsy specimens were stained with hematoxylin-eosin, and assessed by the same dermatopathologist. Patients were also clinically assessed for partial clearance (the clearance of 1 or more lesions treated with imiquimod). In addition, patients treated with imiquimod were clinically assessed for clearance 1 year after treatment.DRUG LABELING AND RANDOMIZATIONThis study was double-blind. The same packaging was used for the imiquimod and vehicle creams, and neither clinicians nor patients were aware of which sachets contained imiquimod. Each sachet was coded and the key to the codes was held by 3M Medica. Each patient was randomly assigned a number that was paired with a box containing 12 sachets. Each box had a 2-part label and the date of attribution, patient number, storage directions, and date of expiration were recorded on both parts of the label. To verify distribution, one part of the label was torn off and retained in the patient's records each time a box of sachets was given to a patient.POSTTRIAL TREATMENTPatients who had received vehicle cream were given the option of applying 5% imiquimod cream 3 times per week for a further 12 weeks. All patients with AK lesions that had not resolved by the end of the study received cryotherapy treatment.STATISTICSThe lesion clearance rates in imiquimod- and vehicle-treated patients were compared using the Fisher exact test.RESULTSSTUDY SUBJECTSOf the 52 patients (14 women and 38 men) screened over a period of 1 month, 31 had skin type II and 21 had skin type III on the Fitzpatrick scale. The mean age of patients was 68 years (range, 51-91 years). Histologic diagnosis showed that 6 patients (18%) in the imiquimod treatment group of 34 patients had been misdiagnosed as having AK. One (3%) had spindle cell carcinoma, 2 (6%) had Bowen disease, and 3 (9%) had seborrheic keratosis. They were excluded from the study before treatment started, as well as 1 patient whose age was over the limit of 85 years. Two other patients (6%) were excluded during the study because of noncompliance. In the control group of 18 patients, 5 (28%) were diagnosed as having spindle cell carcinoma; 4 (22%), seborrheic keratosis; and 1 (6%), Bowen disease. They were excluded before treatment started, and 2 (11%) were excluded during the study for noncompliance. The per protocol analysis of the study presented here is therefore based on the 25 remaining patients (74%) in the group treated with imiquimod and the 11 remaining patients (61%) in the control group.The initial physical examinations detected a variety of clinically nonsignificant abnormal conditions, the most common being high cholesterol levels (in 69% of the study participants).Previous treatments received for AK included cryotherapy in 14 (39%) study participants; applications of ointments normally used for wound healing, including panthenol, dexpanthenol, nystatin, and refobacin in 13 (36%); carbon dioxide laser in 2 (6%); abrasion in 1 (3%); 2% salicylic acid in 2 (6%); and corticosteroids in 2 (6%). In the group of 25 patients treated with imiquimod, 10 (40%) had not been previously treated for AK. In the control group of 11 patients, 5 (45%) had not been previously treated for AK.COMPLIANCEIn the control group, all 11 patients who completed the 12-week treatment applied the vehicle cream to lesions 3 times per week for the duration of the study. Of the 25 patients who completed the treatment with imiquimod, 10 (40%) applied the cream 3 times per week for the full 12 weeks; and because of local adverse reactions, 12 (48%) reduced application to 2 times per week for an average of 5.25 weeks (range, 2-10 weeks) and 6 (24%) reduced application to 1 time per week for 3.5 weeks (range, 1-6 weeks). One patient in the imiquimod-treated group took a rest period after 4 weeks of treatment because of severe local adverse reactions. This patient did not apply cream for 10 days. All vehicle-treated patients and 24 (96%) of the 25 imiquimod-treated patients completed the trial without rest periods.EFFICACY ANALYSISAnalyzed on a per protocol basis, 21 (84%) of the 25 patients in the group treated with imiquimod were diagnosed as having complete clinical clearance of AK lesions (95% confidence interval, 64%-95%). Lesions were diagnosed as clinically resolved at week 9 in 4 (19%) of these 21 patients; at week 12 in 11 (52%); and at week 14 in 6 (29%), 2 weeks after the final application of imiquimod. Partial clearance was reported by 2 (8%) of the 25 patients treated with imiquimod; 1 had a reduction of approximately 50% in AK lesion size; and another had a reduction of approximately 75%. No change in the size or number of lesions was observed in the remaining 2 patients (8%) in this group. By contrast, treatment with the vehicle cream had no effect on the size or number of AK lesions in the 11 patients in the control group.To provide the 95% power needed to detect a significant difference in lesion clearance rates, a minimum of 24 patients treated with imiquimod and 12 control patients were required. As only 11 control patients completed the study, calculations were based on 94% power. Analysis using the Fisher exact test showed a highly significant difference between the clearance rates of the imiquimod- and vehicle-treated groups (P<.001).The clearance rate was 100% (15 of 15) in patients who initially treated AK lesions with imiquimod 3 times per week and who reduced applications to twice and/or once per week. The clearance rate was 60% (6 of 10) in patients who applied imiquimod 3 times per week for 12 weeks.HISTOLOGICAL FINDINGSIn all patients, AK lesions clinically diagnosed as resolved at week 14 were also histologically confirmed as resolved.LONG-TERM CLEARANCE RATEOne year after treatment the clinical recurrence rate in patients treated with imiquimod was approximately 10% (2/25). Only 1 patient in this group was not examined for recurrence.ADVERSE EFFECTSAll patients treated with imiquimod experienced mild, moderate, or severe adverse effects. They included erythema, edema, induration, vesicles, erosion, ulceration, excoriation or flaking, and scabbing (Figure 1). The percentage of patients who reported adverse effects peaked during week 6 of treatment and then declined (Figure 2). Severe erythema was the most frequently reported severe adverse effect (Figure 1). However, by week 9 the majority of cases reported were of moderate intensity (Figure 3). The number and intensity of cases of erythema declined during the remainder of the study. The number of patients who experienced adverse effects in the control group was low compared with that in the imiquimod-treated group (Figure 2). The only reactions reported by control patients were mild erythema, flaking, ulceration, and scabbing.Figure 1.Type, intensity, and frequency of adverse effects reported by patients treated with imiquimod.Figure 2.Percentage of imiquimod- and vehicle-treated patients who experienced adverse effects during the study.Figure 3.Number and severity of cases of erythema reported by patients treated with imiquimod during treatment and 2 weeks after treatment.The investigator also asked patients at each clinic visit if they had experienced any systemic adverse effects; none were reported.COMMENTApplications of 5% imiquimod cream resolved a significantly higher number of AK lesions than applications of vehicle cream (P<.001). In the per protocol analysis, treatment resolved all lesions in 84% of patients, with 100% clearance in the patients who reduced the frequency of application from 3 times to 1 or 2 times per week for 3 to 5 weeks because of erythema. Imiquimod was therefore an effective patient-applied therapy for AK, particularly for those who had a brisk inflammatory response to treatment. The scarring and discoloration associated with toxic or irritating therapies were minimal and the recurrence rate after treatment was low.Imiquimod treatment caused adverse effects in all patients. However, not one of them failed to complete the study due to treatment side effects and only one requested a rest period. Treatment with 5% imiquimod cream was therefore well tolerated. In our practice, patients diagnosed as having AK who have been treated with both fluorouracil and imiquimod have said that they did not experience with imiquimod the stinging and pain they associated with fluorouracil. For this reason, many expressed a preference for imiquimod; but this evidence is anecdotal, and further studies comparing imiquimod treatment with other therapies such as fluorouracil and cryotherapy are needed.The frequency of application of imiquimod was reduced only in patients who experienced severe adverse effects. However, patients in this subgroup had the highest rates of clearance. Those who treated their AK lesions 3 times per week for 12 weeks had the lowest clearance rates but also had fewer and less severe adverse effects. It is therefore possible that inflammation at the site of treatment is necessary for imiquimod to be effective. Preclinical studies in the mouse have shown that application of imiquimod to the skin up-regulates the production of TNF-α and interleukin 12 messenger RNA, suggesting that treatment leads to an increased concentration of inflammatory cytokines in the dermis.The spontaneous regression of basal cell carcinomaand genital warts in patients treated with imiquimodwas also related to the up-regulation of TNF-α and other proinflammatory TH1 cytokines. The proteases, oxygen radicals, and nitric oxide produced by TNF-α–activated macrophages can cause localized tissue destruction. Perforin and granzymes released from IFN-α–stimulated natural killer cells can also cause tissue damage. These substances whose release is triggered indirectly by imiquimod applications may cause adverse effects such as the erythemas, itching, and scabbing observed in this study and in others where imiquimod has been used.Clearly, further studies are needed to investigate the relationship between the inflammatory response to imiquimod and the clearance of AK lesions.Imiquimod has been used successfully in the treatment of NMSCs, including basal cell carcinoma,Bowen disease,and AK.Nonmelanoma skin cancers account for a high proportion of newly diagnosed cancers in the United States, but SCC is responsible for the majority of NMSC-related deaths. Early and effective treatment of AK lesions before progression to SCC would therefore dramatically reduce the number of NMSC-associated deaths. This study shows that imiquimod is a well-tolerated and effective treatment for AK, with a low recurrence rate after treatment.DSPrestonRSSternNonmelanoma cancers of the skin.N Engl J Med.1992;327:1649-1662.STGuenthnerRMHurwitzLJBuckelHRGrayCutaneous squamous cell carcinomas consistently show histologic evidence of in situ changes: a clinicopathologic correlation.J Am Acad Dermatol.1999;41:443-448.JMDodsonJde SpainJEHewettDPClarkMalignant potential of actinic keratoses and the controversy over treatment: a patient-oriented perspective.Arch Dermatol.1991;127:1029-1031.SJSalascheEpidemiology of actinic keratoses and squamous cell carcinoma I.J Am Acad Dermatol.2000;42(1, pt 2):4-7.SMDinehartThe treatment of actinic keratoses.J Am Acad Dermatol.2000;42 (1, pt 2):25-28.LEdwardsAFerenczyLEronSelf-administered topical 5% imiquimod cream for external anogenital warts.Arch Dermatol.1998;134:25-30.EStockflethTMeyerBBenninghoffEChristophersSuccessful treatment of actinic keratosis with imiquimod cream 5%: a report of 6 cases.Br J Dermatol.2001;144:1050-1058.MAStanleyMechanism of action of imiquimod.Papillomavirus Rep.1999;10(2):23-29.KRBeutnerJKGeisseDHelmanTLFoxAGinkelMLOwensTherapeutic response of basal cell carcinoma to the immune response modifier 5% imiquimod cream.J Am Acad Dermatol.1999;41:1002-1007.AMackenzie-WoodSKossardJde LauneyBWilkinsonMLOwensImiquimod 5% cream in the treatment of Bowen's disease.J Am Acad Dermatol.2001;44:462-470.IAhmedJBerth-JonesImiquimod: a novel treatment for lentigo maligna.Br J Dermatol.2000;143:843-45.RBuckleyKSmithTopical imiquimod therapy for chronic giant molluscum contagiosum in a patient with advanced human immunodeficiency virus 1 disease.Arch Dermatol.1999;135:1167-1169.URHenggeSEsserTSchultewolterSelf-administered topical 5% imiquimod for the treatment of common warts and molluscum contagiosum.Br J Dermatol.2000;143:1026-1031.EStockflethJRöwertRArndtTMeyerEChristophersDetection of human papillomavirus and response to topical 5% imiquimod in a case of stucco keratosis.Br J Dermatol.2000;143:846-850.SCThompsonDJolleyRMarksReduction of solar keratoses by regular sunscreen use.N Engl J Med.1993;329:1147-1151.SKTyringImmune response modifiers: a new paradigm in the treatment of human papillomavirus.Curr Ther Res Clin Exp.2000;61:584-596.DAWongGABishopMALowesBCookeRSBarnetsonGMHallidayCytokine profiles in spontaneously regressing basal cell carcinomas.Br J Dermatol.2000;143:91-98.MKKagyRAmonetteThe use of imiquimod 5% cream for the treatment of superficial basal cell carcinomas in a basal cell nevus syndrome patient.Dermatol Surg.2000;26:577-579.Accepted for publication June 14, 2002.We thank 3M Pharmaceuticals for the financial support of this study.We thank Joanne Marks, PhD, and Caroline Magee, PhD, for assisting us in the preparation of the manuscript.Corresponding author and reprints: Eggert Stockfleth, MD, Department of Dermatology, Klinikum Charité Mitte, Humbolt Universität Berlin, Schumannstrasse 20/21, 10117 Berlin, Germany (e-mail: e.stockfleth@web.de). TI - A Randomized, Double-blind, Vehicle-Controlled Study to Assess 5% Imiquimod Cream for the Treatment of Multiple Actinic Keratoses JF - JAMA Dermatology DO - 10.1001/archderm.138.11.1498 DA - 2002-11-01 UR - https://www.deepdyve.com/lp/american-medical-association/a-randomized-double-blind-vehicle-controlled-study-to-assess-5-8LLKiGyxnh SP - 1498 EP - 1502 VL - 138 IS - 11 DP - DeepDyve ER -